Epidermal growth factor receptor (EGFR) inhibition improves survival of head and neck squamous cell carcinoma (HNSCC) patients, but the overall efficacy is limited, and particularly when given in one of its indications (cetuximab single-agent in chemotherapy-refractory HNSCC) responses are low and prognosis is dismal. Cancer stem cells (CSC) have been implicated in resistance to anticancer therapies. Using an advanced patient-derived xenograft HNSCC model we have documented accumulation of CSC subpopulations after EGFR inhibitors, and have hypothesized that CSC are thus responsible for tumor recurrence. These CSC showed 500-fold over expression of the Hedgehog pathway compared with the non-CSC, proliferating cells. In addition, we observed that cetuximab induced SIP1/ZEB2 and TWIST that are promoters of epithelial to mesenchymal transition (EMT), also associated to resistance to EGFR inhibitors in HNSCC. Finally, we determined in vivo that a combination of EGFR and Hedgehog inhibitors decreased the CSC population, blocked EMT, and prevented re-growth of HNSCC tumors. The goal of this proposal is to conduct a rationally- driven combination Phase 1 study of EGFR and Hedgehog inhibitors in refractory HNSCC patients. The trial will include a cetuximab lead-in period of two weeks, followed by the combination of cetuximab plus IPI-926 starting in week 3. By conducting three seriated tumor biopsies (pre-treatment [d0], post-lead-in [C1D14], and post-combination [C1D28]) we will test our hypotheses that 1) CSC accumulate after conventional therapy, 2) EGFR inhibitors induce EMT, and 3) the combination of EGFR and Hedgehog inhibitors induces an antitumor effect by inhibiting both proliferating cells and CSC, and preventing EMT. The candidate is ideally positioned to drive this translation from the bench to the clinic given his involvement as principal investigator in the first-in- human study of IPI-926, his experience in the field of CSC and his unique expertise in conducting studies with multiple tumor testing with pharmacodynamic endpoints.